brain research 1580 (2014) 219232

Available online at www.sciencedirect.com

www.elsevier.com/locate/brainres

Oxytocin and postpartum depression: Delivering

on what's known and what's not
Sohye Kima,b,c, Timothy A. Soekena, Sara J. Cromera, Sheila R. Martineza,b,
Leah R. Hardya,b, Lane Strathearna,b,c,d,n
a

Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

Attachment and Neurodevelopment Laboratory, Children's Nutrition Research Center, Department of Pediatrics, Baylor
College of Medicine, 1100 Bates Street, Suite 4004, Houston, TX 77030, USA
c
Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, One Baylor Plaza, Houston,
TX 77030, USA
d
The Meyer Center for Developmental Pediatrics, Texas Children's Hospital, 8080 N. Stadium Drive, Houston, TX 77054,
USA
b

art i cle i nfo

ab st rac t

Article history:

The role of oxytocin in the treatment of postpartum depression has been a topic of growing

Accepted 7 November 2013

interest. This subject carries important implications, given that postpartum depression can

Available online 14 November 2013

have detrimental effects on both the mother and her infant, with lifelong consequences for

Keywords:

infant socioemotional and cognitive development. In recent years, oxytocin has received

Postpartum depression

attention for its potential role in many neuropsychiatric conditions beyond its well-

Oxytocin

described functions in childbirth and lactation. In the present review, we present available

Treatment

data on the clinical characteristics and neuroendocrine foundations of postpartum

Maternal caregiving

depression. We outline current treatment modalities and their limitations, and proceed

Infant

to evaluate the potential role of oxytocin in the treatment of postpartum depression. The
aim of the present review is twofold: (a) to bring together evidence from animal and
human research concerning the role of oxytocin in postpartum depression, and (b) to
highlight areas that deserve further research in order to bring a fuller understanding of
oxytocin's therapeutic potential.
This article is part of a Special Issue entitled Oxytocin and Social Behav.
& 2013 Elsevier B.V. All rights reserved.

1.

Introduction

Postpartum depression (PPD) is a debilitating disorder affecting

at least one in seven American women annually (Gaynes
et al., 2005). PPD impairs the mother's capacity for adaptation
n

following childbirth, posing numerous challenges to the motherinfant relationship and the infant's subsequent development
(Murray and Cooper, 1997). Despite the increased attention
given to PPD over the past several decades, PPD is currently
conceptualized and treated in much the same manner as

Corresponding author at: Baylor College of Medicine/Texas Children's Hospital, Department of Pediatrics, Attachment and
Neurodevelopment Laboratory, Children's Nutrition Research Center, 1100 Bates St, Suite 4004-B, Houston, TX 77030, USA.
Fax: 1 713 798 7009.
E-mail address: lanes@bcm.edu (L. Strathearn).
0006-8993/$ - see front matter & 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.brainres.2013.11.009

220

brain research 1580 (2014) 219232

non-postpartum depression, often leading to less than optimal

treatment outcomes. In a separate but related line of research, a
substantial interest has centered around oxytocin (OT), a neuropeptide hormone critically implicated in the transition to and
adjustment during early motherhood. The past two decades
have witnessed a surge of clinical trials evaluating OT's therapeutic potential in a wide range of psychiatric disorders, and
increasing attention is now directed to PPD as another clinical
syndrome for which OT may be of therapeutic benet. In the
present review, we draw upon available data from animal and
human research to critically evaluate the potential role of OT in
treating PPD. Our goal is to bring together relevant evidence that
may elucidate the potential of OT as a therapeutic agent for PPD,
while highlighting areas where further research is necessary.

2.

Postpartum depression

2.1.

Denition and diagnosis

PPD is dened as the presence of a major depressive episode

following childbirth, although there remains controversy
regarding the time criterion pertaining to its onset. The
Diagnostic and Statistical Manual of Mental Disorders (DSM)IV utilized the specier with postpartum onset to limit the
diagnosis of PPD to depressive episodes manifesting within
4 weeks post delivery (American Psychiatric Association, 2000),
while the newly released DSM-5 uses the specier with
peripartum onset to encompass depressive episodes present
during pregnancy (American Psychiatric Association, 2013). In
contrast to the DSM, the International Classication of Diseases (ICD)-10 classies depression as associated with the
puerperium if the onset is within 6 weeks postpartum (World
Health Organization, 1992). In the face of a lack of consensus,
two large-scale epidemiological studies have demonstrated
that women's risk for psychiatric illness increased from childbirth to approximately 3 months postpartum; the risk
increased up to 5 months postpartum specically for depression (Kendell et al., 1987; Munk-Olsen et al., 2006). In consideration of the epidemiological ndings and challenges in
practical clinical applications, some experts have recommended that the time criterion be extended to 3 to 6 months
postpartum (Elliott, 2000; Wisner et al., 2010).
As with non-postpartum depression, depressive symptoms must be present for more than 2 weeks to warrant
the diagnosis of PPD. Common symptoms include depressed
mood, loss of interest and energy, changes in sleep or eating
patterns, diminished ability to think or concentrate, feelings
of worthlessness, and recurrent suicidal ideations. While not
currently a part of diagnostic criteria, anxiety is considered a
prominent feature of PPD, present in approximately half of
women diagnosed with PPD (Ross et al., 2003). In severe cases,
PPD can be accompanied by psychotic features which may
include delusions or command hallucinations to harm the
infant (American Psychiatric Association, 2013).

2.2.

Prevalence and risk factors

Prevalence estimates of PPD range widely from 5 to 25%

(Gavin et al., 2005), primarily due to the variability in the

criteria used, particularly the time criterion. However, ndings from meta-analytic and systematic reviews converge to
point to a more precise estimate of 10 to 15% (Gaynes et al.,
2005; O'Hara and Swain, 1996), translating to approximately
600,000 women in the United States annually. This is distinguished from the postpartum blues, a mild and transient
mood disturbance following childbirth, commonly experienced by up to 80% of postpartum women (Beck, 2006;
Buttner et al., 2012). The risk of PPD increases with a history
of prenatal depression, prenatal anxiety, or PPD (Beck, 2001;
Robertson et al., 2004; Wisner and Wheeler, 1994). Stressors
during pregnancy and the early postpartum, including perinatal complications, preterm birth, or infant health problems
(Blom et al., 2010; Robertson et al., 2004; Sit and Wisner, 2009),
also serve to increase the risk of PPD, as do poverty, low social
support, and adolescent motherhood (Beck, 2001; O'Hara and
Swain, 1996; Robertson et al., 2004; Troutman and Cutrona,
1990; Wang et al., 2011). PPD lasts for more than 7 months in
over half of affected women (Sit and Wisner, 2009).
While studies have demonstrated a high heritability of
depressive disorders (Sullivan et al., 2000), evidence is less
conclusive concerning PPD (Corwin et al., 2010). The only
published twin study of PPD is one by Treloar et al. (1999),
who demonstrated that genetic factors accounted for 25% of
variance in the onset of PPD in 838 Australian female twin
pairs. Three family studies exist to date and suggest that the
rate of PPD increases in female siblings of women with
unipolar (Forty et al., 2006; Murphy-Eberenz et al., 2006) or
bipolar depression (Payne et al., 2008). Although informative,
these few studies have been criticized by some for methodological shortcomings (e.g., failure to distinguish between PPD
and postpartum blues or to control for other psychiatric
comorbidity; Corwin et al., 2010), particularly in light of the
lack of association shown by other groups between a
woman's familial history of depression and her development
of PPD (Bloch et al., 2005; Dennis et al., 2004). Studies of
genetic markers have also been underway and have highlighted the role of the polymorphisms of three candidate
genes, the serotonin transporter, monoamine oxidase A, and
catechol-O-methyltransferase genes (Doornbos et al., 2009;
Sanjuan et al., 2008), although complex genetic and epigenetic interactions remain to be explored.

2.3.

Neuroendocrine considerations

Elucidating the neuroendocrinology of PPD has been a challenge

in the eld due to normative and adaptive neuroendocrine
changes that take place during pregnancy and postpartum.
Gonadal steroid hormones have received attention, as levels of
estradiol and progesterone drop drastically following parturition, often coinciding with the onset of postpartum blues or PPD
symptoms. A noteworthy study by Bloch et al. (2000) found that
the simulation of gonadal withdrawal precipitated depressive
symptoms in euthymic women with a history of PPD, supporting the potential contribution of hypogonadism to the onset of
PPD. However, the relationship between hypogonadism and
PPD has been disputed by many others (Abou-Saleh et al., 1998;
Harris et al., 1996; Klier et al., 2007; Zonana and Gorman, 2005).
Currently, there is no consistent evidence that a decrease in
absolute concentrations of gonadal hormones triggers PPD,

brain research 1580 (2014) 219232

although available data suggest that PPD may manifest in

women who are vulnerable to uctuations in gonadal hormone
levels (Workman et al., 2012).
Dysregulation of the hypothalamicpituitaryadrenal (HPA)
axis has also garnered interest for its potential role in the
etiology of PPD. The HPA system undergoes numerous changes
during pregnancy and postpartum (Lightman et al., 2001; Tu
et al., 2006). Adreno-corticotropic hormone levels increase during
pregnancy, and cortisol reaches its peak at the end of pregnancy
as the placental corticotropin-releasing hormone (CRH) levels
rise, before dropping rapidly at parturition (Kammerer et al.,
2006; Yim et al., 2009). There have been reports that women with
PPD demonstrate more extreme changes in the activity of the
HPA axis during pregnancy and postpartum (Jolley et al., 2007;
Taylor et al., 2009), though directionality has been inconsistent,
with increased (Lommatzsch et al., 2006; Okano and Nomura,
1992) or decreased cortisol levels being documented (Groer and
Morgan, 2007; Jolley et al., 2007). Indeed, some have proposed
that different subtypes of PPD may exist, underpinned by distinct
genetic predispositions and differential regulation patterns
(i.e., hypo- vs. hyper-regulation) of the HPA axis (Kammerer
et al., 2006).
OT has received less interest than gonadal or stress hormones as a potential etiologic factor in PPD, although it has
attracted attention for its involvement in breastfeeding difculties often present in PPD (Stuebe et al., 2012). It is well known
that OT is critically implicated in milk letdown (Pang and
Hartmann, 2007). The documented association between breastfeeding difculties and PPD (Dennis and McQueen, 2009;
Taveras et al., 2003; Watkins et al., 2011) is worthy of attention
(Skalkidou et al., 2010). To date, only one study (Stuebe et al.,
2013) has examined OT as part of the link between lactation
failure and PPD. In a group of mothers intending to breastfeed,
the authors found that OT levels were inversely correlated with
depressive symptoms in both the third trimester and at 8 weeks
postpartum, corroborating and extending earlier ndings by
Skrundz et al. (2011). The authors also documented that OT
release was reduced in depressed mothers during breastfeeding
compared to non-depressed mothers, although no difference
was found between the two groups in breastfeeding duration or
intensity. Stress-attenuating effects of breastfeeding deserve
consideration here (Heinrichs et al., 2001; Stuebe et al., 2012).
Compared to their non-breastfeeding counterparts, breastfeeding women demonstrated attenuated HPA response to stressors
(Altemus et al., 1995). Furthermore, cortisol levels decreased in
breastfeeding women during lactation (Amico et al., 1994), while
mood scores improved following lactation (Heinrichs et al.,
2001). Animal models (Neumann, 2003) have suggested that
disruptions of the OT system may be implicated in the observed
relations between breastfeeding, stress regulation, and mood,
which is of particular relevance to PPD given that all three
components become disrupted in many affected women
(Heinrichs et al., 2001; Stuebe et al., 2012).

3.

Maternal caregiving in postpartum depression

PPD is well known to have deleterious effects on the development of the offspring. Reports show that children of
depressed mothers are at risk for a wide range of cognitive,

221

emotional, behavioral, and medical problems. Cognitively,

they are likely to have lower IQ scores, attention problems,
and special educational needs (Hay et al., 2001). Emotionally,
they are susceptible to various forms of psychopathology
including mood disorders, anxiety disorders, and substance
use disorders (Apter-Levy et al., 2013; Murray et al., 2011;
Schwartz et al., 1990). Behavioral problems are also prevalent,
at times warranting the diagnoses of conduct disorder or
oppositional deant disorder (Alpern and Lyons-Ruth, 1993;
Dawson et al., 2003). They are also often high utilizers of
pediatric emergency services, while frequently missing outpatient pediatric visits (Flynn et al., 2004). Many of these
adverse developmental outcomes have been associated with
impaired maternal caregiving behavior in depression, even
after controlling for the effects of demographic variables
(Azak and Raeder, 2013; NICHD Early Child Care Research
Network, 1999).
A large number of studies have highlighted that mothers
with PPD are slow to read, decipher, and respond to their
infants' signals (see reviews, Field, 2010; Tronick and Reck,
2009). While some depressed mothers are withdrawn, passive, and under-stimulating, others are intrusive, hostile, and
over-stimulating (Lovejoy et al., 2000; Malphurs et al., 1996;
Weikum et al., 2013). This provides infants with fewer and
shorter moments of reciprocal engagement, joint attention,
and shared affect (Feldman, 2007; Weinberg and Tronick,
1998). Infants are also given fewer opportunities to experience repair following moments of disrupted engagement
(Jameson et al., 1997). Such disruptions in the early mother
infant relationship may serve as a precursor to insecure
infant attachment (Mills-Koonce et al., 2008; Stern, 1995),
which has longitudinally been linked to numerous adverse
developmental outcomes (Sroufe et al., 2005), including the
cognitive, emotional, and behavioral outcomes described
above. One recent study (Laurent and Ablow, 2013) documented that maternal brain responses were altered in women
with PPD. While viewing images of their own infants,
mothers with PPD displayed blunted activity in brain regions
known to be central for emotional responsiveness, empathy,
and reward (e.g., anterior cingulate, orbitofrontal cortex,
insula, and striatum).
Frequently, the impaired motherinfant relationship is
further compromised by breastfeeding difculties often experienced in women with PPD. While breastfeeding provides one of
the earliest opportunities for the mother to establish an
intimate bond with her infant, many depressed mothers report
dissatisfaction with breastfeeding (Dennis and McQueen, 2007)
and discontinue breastfeeding between 4 to 16 weeks postpartum (McLearn et al., 2006; Paulson et al., 2006).

4.

Current treatment of postpartum depression

4.1.

Pharmacotherapy

4.1.1.

Antidepressant medication

PPD is currently treated in much the same manner as nonpostpartum depression, with selective serotonin reuptake
inhibitors (SSRIs) as the rst-line of pharmacotherapy. As in
non-postpartum depression (Cipriani et al., 2007), SSRIs

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brain research 1580 (2014) 219232

are efcacious in targeting depressive symptoms in PPD.

A review of available randomized controlled clinical trials
show that SSRIs improved mood in 43 to 88% of women with
PPD (Appleby et al., 1997; Bloch et al., 2012; Misri et al., 2004;
Sharp et al., 2010; Wisner et al., 2006; Yonkers et al., 2008),
which are similar to rates reported for non-postpartum
depression (Kirsch et al., 2008); 37 to 65% of treated women
achieved remission of depressive symptoms (De Crescenzo
et al., 2013). Despite the demonstrated efcacy, factors unique
to pregnancy and the postpartum period complicate the
antidepressant treatment of PPD (Ellfolk and Malm, 2010;
Yonkers et al., 2009). Many healthcare providers are reluctant
to engage patients in pharmacotherapy due to concerns about
fetal or infant exposure to antidepressants, and three-quarters
of women diagnosed with PPD are indeed left untreated
(Bennett et al., 2004). Pregnant or postpartum women similarly
show low acceptability of antidepressant medications (Chabrol
et al., 2004), with available SSRI trials reecting high drop-out
rates (Appleby et al., 1997; Wisner et al., 2006; Yonkers et al.,
2008). Medications may also be prescribed and used at subtherapeutic doses (Bennett et al., 2004; Epperson et al., 2003),
which may be a particular concern since women with PPD
require higher doses of antidepressant agents for a longer
duration to experience relief of symptoms (Dawes and
Chowienczyk, 2001; Hendrick et al., 2000).
Data on the effects of antidepressant treatment on
maternal functioning are limited. Only one group
(Logsdon et al., 2009, 2011) has provided relevant data,
demonstrating that antidepressants were effective in
enhancing maternal role-gratication throughout the rst
postpartum year, but not maternal self-efcacy, overall
maternal role functioning, or the quality of the mother
infant relationship. The literature on fetal or infant exposure to SSRIs is large and growing. As per a recently
published report from the American Psychiatric Association (APA) and the American College of Obstetricians and
Gynecologists (ACOG; Yonkers et al., 2009), the accumulated data are in support of small but signicant associations between SSRI use during pregnancy and preterm
delivery (i.e., o37 weeks gestation) as well as small-forgestational-age birth weight (i.e., o10% of age-adjusted
birth weight). Antidepressant use was generally not associated with major congenital malformations in the infant,
although use during the third trimester was linked to
transient poor neonatal outcomes (e.g., irritability,
jitteriness).

4.1.2.

Hormonal therapy

Estradiol therapy is a novel treatment that targets the ux of

gonadal hormones that may render a subset of women vulnerable to depression in the postpartum period (Bloch et al., 2000;
Moses-Kolko et al., 2009). Growing data suggest that estradiol
therapy has promising antidepressant properties, with reported
response and remission rates exceeding those of SSRIs. Within
the rst month of a double-blinded, placebo-controlled trial
(Gregoire et al., 1996), women treated with estrogen patches
showed greater and more rapid improvements in their depressive symptoms compared to those treated with placebo patches.
Similar improvements were shown in another study (Ahokas
et al., 2001), in which 83% of severely depressed women reached

remission within 2 weeks of treatment with sublingual estradiol.

Notably, decreases in women's depression scores were inversely
correlated with increases in their serum estrogen levels, and
available data suggest that estradiol therapy was well tolerated
with low dropout rates. However, estradiol therapy may interfere
with breastfeeding, a consideration important in the treatment
of PPD (Fitelson et al., 2010; Moses-Kolko et al., 2009). Although
early data suggested that synthetic progesterones may be
therapeutic for PPD, this view has since been challenged and
the use of progesterones is not recommended (Dennis et al.,
2008). Currently, no data exist on the effects of hormonal therapy
on maternal behavior.

4.2.

Psychological interventions

Psychological interventions that have been empirically studied for the treatment of PPD include interpersonal psychotherapy (IPT; Grote et al., 2009; Mulcahy et al., 2010),
cognitive behavioral therapy (CBT; Chabrol et al., 2002;
Wiklund et al., 2010), psychodynamic therapy (Bloch et al.,
2012; Cooper et al., 2003), and non-directive counseling
(Milgrom et al., 2005; Murray et al., 2003). Several metaanalyses exist to date and suggest that psychological interventions are efcacious in reducing depressive symptoms
(Cuijpers et al., 2008; Dennis and Hodnett, 2007; Lumley et al.,
2004; Sockol et al., 2011) at rates similar to those of antidepressant medications (De Crescenzo et al., 2013; Sockol
et al., 2011). No conclusive data exist to suggest the superiority of one psychotherapy modality to another in the
treatment of PPD (Fitelson et al., 2010), although there is
some evidence that IPT, which directly addresses interpersonal problems (e.g., role transitions, relational conicts), may
be more efcacious than CBT, which targets maladaptive
depressogenic cognitions (Bledsoe and Grote, 2006; Sockol
et al., 2011).
However, as with pharmacotherapy, a mere decrease in
depressive symptoms is often not enough to enhance maternal functions (Forman et al., 2007; Murray et al., 2003).
Psychological interventions without an explicit focus on the
motherinfant relationship were effective in reducing maternal parenting stress, without beneting maternal or infant
behavior (Forman et al., 2007; O'Hara et al., 2000). Interventions that actively incorporated the motherinfant relationship as a focus generally yielded some improvement in this
domain (Clark et al., 2003; O'Hara and McCabe, 2013; Poobalan
et al., 2007). However, therapeutic gains were not sustained
on longitudinal follow-ups and did not generalize to infants'
cognitive or behavioral outcomes, with the exception of one
study in which extensive and prolonged therapy was implemented (Cicchetti et al., 2000).
Current APA and AGOC guidelines recommend psychotherapy as the rst-line of treatment for mild to moderate
depression, although antidepressant medications are recommended in the presence of moderate to severe depressive
symptoms, particularly in women with a history of recurrent
depression (Kim et al., 2010; Yonkers et al., 2009). The
acceptability of psychotherapy is reported to be high in
postpartum women (Chabrol et al., 2004) and psychotherapy
is often preferred to antidepressants in this population
(Pearlstein et al., 2006; Turner et al., 2008).

brain research 1580 (2014) 219232

5.

Oxytocin: A novel therapeutic for postpartum

depression?

As the preceding review suggests, currently available treatments of PPD are promising in reducing depressive symptoms, but are less effective in improving the motherinfant
relationship. OT has emerged as a potentially viable treatment option in this context, given its role in regulating the
onset and maintenance of maternal behavior, along with its
antidepressant and anxiolytic properties.
OT is a nonapeptide synthesized in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the
hypothalamus and released into the bloodstream from the
neurohypophysis (Gimpl and Fahrenholz, 2001; Insel, 2010).
OT receptors are located throughout the brain including
regions known to be critical for the expression of maternal
behaviors, such as the ventromedial nucleus of the hypothalamus, central nucleus of the amygdala, medial preoptic area
(MPOA), bed nucleus of the stria terminalis (BNST), and
ventral tegmental area (VTA). OT is also secreted in small
amounts by numerous peripheral tissues such as the uterus,
placenta, corpus luteum, testis, and heart (Gimpl and
Fahrenholz, 2001). For many decades, OT was well recognized
for its peripheral actions, including uterine contraction in
parturition and milk ejection during lactation (Insel, 2010;
Ross and Young, 2009), though it is now regarded a key
neuroregulator implicated in social and stress-related disorders on one hand and maternal behavior on the other (Bartz
and Hollander, 2006; Neumann and Landgraf, 2012). To assist
in evaluating the potential of OT as a therapeutic agent for
PPD, we examine available animal and human research on
the role of OT in (a) anxiety- and depressive-like behavior and
in (b) maternal functioning.

5.1.

Antidepressant and anxiolytic effects of oxytocin

5.1.1.

Animal studies

An antidepressant effect of OT was rst reported by Arletti

and Bertolini (1987), who demonstrated that acute and
repeated intra-peritoneal injections of OT in mice reduced
the immobility time in the forced swim test, a commonly
used index of depressive behavior in animals. Similarly,
subcutaneous OT infusions in rats reduced the escape failures in the learned helplessness test, another widely used
animal model of depression (Nowakowska et al., 2002).
Recently, these results were replicated following intracerebral
administrations of OT (Ring et al., 2010), suggesting that
central or peripheral administrations of OT may have antidepressant properties (Slattery and Neumann, 2010b). In
rats, OT has also been shown to improve other features of
depression (Neumann and Landgraf, 2012), including anhedonia (Liberzon et al., 1997), sexual dysfunction (Melis et al.,
2007), and sleep disturbance (Lancel et al., 2003).
Anxiolytic and stress-attenuating effects of OT have also
been well documented. Anxiogenic stimuli are understood to
increase central OT release in the PVN of the hypothalamus
(Nishioka et al., 1998), central nucleus of the amygdala
(Ebner et al., 2005), and lateral septum (Ebner et al., 2000),
which subsequently functions to dampen stress response by

223

modulating the activity of the HPA axis (Engelmann et al.,

2004; Neumann et al., 2000). OT knockout mice showed
increased stress-induced fos expression in the medial amygdala and BNST, heightened CRH mRNA expression in the
PVN, and elevated corticosterone release following exposure
to stressors (Amico et al., 2008; Nomura et al., 2003). Furthermore, intracerebroventricular infusions of OT decreased the
molecular and neuroendocrine responses of the HPA axis and
attenuated anxiety-like behaviors in female rats, while
administration of the OT receptor antagonist produced opposite results (Slattery and Neumann, 2010a; Windle et al.,
2004).
While mechanisms of the antidepressant and anxiolytic
effects of OT remain to be further elucidated, available
evidence suggests that the effects may be produced in part
by the interactions between the serotonergic, corticotropinreleasing factor (CRF), and OT systems (Neumann and
Landgraf, 2012). OT release is understood to activate OT
receptors in serotonergic neurons of the raphe nuclei to yield
antidepressant and anxiolytic effects (Yoshida et al., 2009),
whereas stimulation of serotonin release activates CRF and
OT neurons in the hypothalamus (Javed et al., 1999), a
mechanism that may underlie antidepressant properties of
the SSRIs (Emiliano et al., 2007).

5.1.2.

Human studies

OT-related dysfunctions have been examined in depressed

patients, although results remain inconclusive. Some groups
have shown that peripheral OT concentrations were lower in
depressed patients, particularly female patients (Ozsoy et al.,
2009), compared to controls (Frasch et al., 1995; Zetzsche et al.,
1996). Another report showed that the severity of patients'
depression and anxiety symptoms was inversely correlated
with their plasma OT levels (Scantamburlo et al., 2007). However, other studies of plasma OT (Cyranowski et al., 2008; van
Londen et al., 1997) and a few available studies of cerebrospinal
uid (CSF) OT (Demitrack and Gold, 1988; Pitts et al., 1995) failed
to document reduced OT levels in depressed patients. Notably,
these studies found a greater variability of OT concentrations in
the patient group (Cyranowski et al., 2008; van Londen et al.,
1997); in one study, a trend toward reduced OT was found only
in a subgroup of patients (Pitts et al., 1995).
Endogenous OT released during breastfeeding (Chiodera
et al., 1991) has been understood to underlie the attenuated
HPA responsiveness and reduced anxiety behavior shown in
lactating women (Heinrichs et al., 2001). However, exogenous
OT administrations in humans have produced equivocal ndings. Intranasal OT was reported to decrease stress responsiveness and anxiety in healthy men (Heinrichs et al., 2003),
reduce levels of salivary cortisol during couple conict in
heterosexual couples (Ditzen et al., 2009), and attenuate fearrelated amygdala reactivity in healthy males and patients with
social anxiety (Kirsch et al., 2005; Labuschagne et al., 2010).
However, these studies failed to document direct effect of
intranasal OT on mood (Kirsch et al., 2005; Labuschagne et al.,
2010). Furthermore, while the majority of the studies were
conducted in men, intranasal OT was shown to enhance fearrelated amygdala reactivity in healthy women (Domes et al.,
2010; but see Rupp et al., 2012 for results in nulliparous women
only), while producing null effects in healthy postpartum

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brain research 1580 (2014) 219232

women (Rupp et al., 2012). Notably, the only available study on

PPD demonstrated that intranasal OT worsened self-reported
mood ratings in this group of women (Mah et al., 2013). A
study observing the use of OT to aid the progress of labor
further showed that OT administration during labor did not
reduce the incidence of PPD in rst-time mothers (Hinshaw
et al., 2008).

5.2.

Oxytocin and maternal behavior

5.2.1.

Animal studies

A large body of research supports the role of OT in the onset

and maintenance of maternal behavior across species. Intracerebroventricular injections of OT induced a full range of
maternal behavior in female virgin rats (Pedersen and Prange,
1979; Pedersen et al., 1982), whereas infusions of OT antagonist inhibited the emergence of maternal behavior in parturient rat dams (Pedersen et al., 1994; van Leengoed et al., 1987).
Similar results were found in mice (McCarthy, 1990) and
sheep (Kendrick et al., 1987; Keverne and Kendrick, 1992).
These ndings are in line with the report that lesions of the
PVN, a main site of OT production in the brain, disrupted the
onset of maternal behavior in rats (Insel and Harbaugh, 1989).
Impaired maternal behavior was similarly found in female
OT knockout mice (Ragnauth et al., 2005; Takayanagi et al.,
2005) and postpartum mutant female mice with reduced OT
neurons in the PVN (Li et al., 1999). Other prominent sites of
OT receptors have also been examined in relation to the
expression of maternal behavior. OT receptor density in the
central nucleus of the amygdala and BNST was shown to be
correlated with the quality of maternal care in rats (Francis
et al., 2000); OT receptor binding density in the nucleus
accumbens was similarly associated with the amount of time
prairie voles spent crouching over pups (Olazabal and Young,
2006).
Another important line of research in this area concerns
the modication of the OT system by early caregiving experiences (Champagne, 2008; Meaney, 2001). A series of experimental and cross-fostering studies demonstrated that female
rats reared by low licking-and-grooming and arched-back
nursing (LG-ABN) mothers showed a reduced density of OT
receptors in brain regions critical for the expression of
maternal behavior, including the MPOA, PVN, and lateral
septum (Champagne et al., 2001, 2003b, 2006). Just like their
mothers, the female rat pups were subsequently seen to
display low levels of LG-ABN behavior with their offspring
when they reached the postpartum period (Champagne et al.,
2003a; Francis et al., 1999). Similarly, non-maternal rearing in
rhesus monkeys was associated with reduced CSF OT levels
across the rst three years of life (Winslow et al., 2003).
Studies on OT-related maternal functions are continuing
to expand. The current understanding is that OT circuits
interact closely with dopaminergic circuits to regulate the
expression of maternal behavior (Shahrokh et al., 2010;
Strathearn, 2011). OT neurons in the PVN and MPOA of
the hypothalamus project to the VTA and nucleus accumbens (Numan and Smith, 1984; Ross et al., 2009a), and the
connections and signals between these regions increase with
the quality of maternal behavior (Champagne et al., 2004;
Shahrokh et al., 2010). The OT-dopamine interactions are

thought to mediate the rewarding and reinforcing properties

of the motherinfant interaction.

5.2.2.

Human studies

Over the past decade, many important advances have been

extended from animal models to humans, elucidating the
central role of OT in human mothering. Peripheral OT levels
in mothers have been consistently associated with naturally
occurring variations in maternal behavior, with high OT
levels during pregnancy and postpartum predicting enhanced
maternal behavior (Atzil et al., 2011; Feldman et al., 2007;
Gordon et al., 2010a, 2010b). Following the work of Meaney
(2001) and Champagne (2008), research in this area has
underscored the interindividual variability of OT-related
functions in mothers. Interactions with infants stimulate
OT release in mothers, but only in a subgroup of mothers
who demonstrate secure attachment (Strathearn et al., 2009),
display sensitivity to emotions and physical sensations
(Strathearn et al., 2012), or exhibit synchronous and affectionate forms of mothering (Feldman et al., 2010a; Kim et al.,
2014). Maternal OT increase during motherinfant interaction has further been correlated with the concurrently
measured OT increase in the infant, supporting an intergenerational link between the OT functions of mother and
infant in humans (Feldman et al., 2010b). Evidence continues
to grow supporting the understanding that women's OT
functions may be modied by their early caregiving experiences. Inverse associations have been reported between
women's levels of CSF OT and the severity and duration of
abuse and neglect to which they were exposed in childhood
(Heim et al., 2009). Studies have further documented low
plasma OT levels in individuals who reported receiving low
levels of parental care (Feldman et al., 2011; Gordon et al.,
2008).
Only a handful of studies have examined the role of OT in
maternal brain responses. Strathearn et al. (2009) found that
mesocorticolimbic dopaminergic reward regions (i.e., ventral
striatum, medial prefrontal cortex) as well as the hypothalamic
OT regions were activated when securely attached mothers
viewed images of their own infants. Similar results were reported
by Atzil et al. (2011), who demonstrated that mothers who
displayed synchronous forms of mothering showed activation
of the ventral striatum, a key reward region, while viewing video
clips of their own infants. Notably, activations in these brain
regions were correlated with the peripheral measures of OT in
these mothers (Atzil et al., 2011; Strathearn et al., 2009). Brain
responses of breastfeeding mothers have also attracted attention, given the role of breastfeeding in endogenous OT production (Chiodera et al., 1991). The only pertinent study to date is
that by Kim et al. (2011), who found that breastfeeding mothers
showed greater activation of the brain regions critical for the
expression of maternal behavior, including the striatal reward
region, in response to their own infants' cries.
Studies have recently begun to examine the role of
exogenous OT administrations in maternal brain responses.
Intranasal administrations of OT were shown to increase
the incentive salience of an unknown infant's laughter in
a group of women, as evidenced by the enhanced connectivity observed between the amygdala and emotion regulation
regions (Riem et al., 2012). Conversely, in response to an

brain research 1580 (2014) 219232

unknown infant's cry, intranasal OT decreased the women's

negative emotional arousal, as reected by reduced amygdala
signals, while increasing activations in the empathy-related
regions (Riem et al., 2011). It is important to note that
intranasal OT further decreased the women's handgrip force
in response to hearing infant's cry, although the effect was
present only in women without early experiences of harsh
parenting (Bakermans-Kranenburg et al., 2012).

5.3.

Oxytocin in the treatment of psychopathology

In addition to its role in regulating the expression of maternal

behavior as reviewed above, a large body of literature has
implicated OT in a much broader range of social behaviors
(Benarroch, 2013; Meyer-Lindenberg et al., 2011), including pair
bonding (Ross et al., 2009b; Schneiderman et al., 2012), interpersonal trust (Kosfeld et al., 2005; Van IJzendoorn and
Bakermans-Kranenburg, 2012), emotion recognition (Lischke
et al., 2012; Perry et al., 2013), and empathy (Hurlemann et al.,
2010; Rodrigues et al., 2009), to name a few. Due to its seemingly
widespread prosocial effects, along with its antidepressant and
anxiolytic properties, OT has gained widespread popularity over
the past decade in the study of normative and psychiatric
populations. A sizable number of trials have investigated its
therapeutic potential in many psychiatric disorders, and many
more trials are underway. To date, clinical trials in which OT
has demonstrated therapeutic benet over placebo include
those of autism spectrum disorder (Anagnostou et al., 2012;
Andari et al., 2010; Guastella et al., 2010), schizophrenia
(Averbeck et al., 2012; Feifel et al., 2010; Modabbernia et al.,
2013; Pedersen et al., 2011), social anxiety (Guastella et al., 2009;
Labuschagne et al., 2010), and post-traumatic stress disorder
(Yatzkar and Klein, 2009).
Despite the considerable excitement that these results
have generated, a more complicated and nuanced picture
emerges upon careful examination of the available data.
Effects of OT reported in many social domains (e.g., social
cognition, prosociality) are often inconsistent or, more precisely, are moderated by contextual and personal factors
(Bartz et al., 2011b; Guastella and MacLeod, 2012; Macdonald
and Macdonald, 2010). The context-dependent nature of the
effects of OT is well demonstrated in a series of studies
conducted on trust, in which exogenous administrations of
OT increased participants' trust of individuals perceived as
part of the in-group, but increased non-cooperation toward
out-group members who were perceived as potential threats
(De Dreu et al., 2010, 2012). The person-dependent nature of
the effects of OT is well captured in a growing number of
studies that demonstrate null effects of exogenous OT in
individuals with adverse early caregiving experiences,
whether assessed by reported severity of childhood abuse,
neglect, or loss (Meinlschmidt and Heim, 2007), memories of
parental love-withdrawal (Riem et al., 2013; van Ijzendoorn
et al., 2011), or recollections of harsh parenting experiences
(Bakermans-Kranenburg et al., 2012). Considering that the
development of one's OT system may be critically modied
by the quality of early caregiving one receives (Champagne,
2008; Meaney, 2001), it is possible that the OT system may
have been altered at a more fundamental level, possibly at
the level of receptors, in individuals with early adverse

225

experiences. The resulting alterations in OT receptor density,

afnity, or functions may underlie the decreased responsivity
that is seen in these individuals upon exogenous administrations of OT (Bakermans-Kranenburg and van IJzendoorn,
2013).
This is of particular relevance in considering the use of OT
in psychiatric patients, since early adverse experiences are
rather common in this population. Not surprisingly, a review
of data suggests that psychiatric patients have produced
variable results in response to exogenous OT administrations,
ranging from improvement (Guastella et al., 2010; Pedersen
et al., 2011) to worsening of symptoms (Bartz et al., 2011a;
Mah et al., 2013), along with some null ndings (Epperson
et al., 1996; Pitman et al., 1993). In some cases, exogenous
administrations of OT have yielded opposing patterns of
results for psychiatric and healthy groups (e.g., Bartz et al.,
2011a; Pincus et al., 2010). This divergence is well reected in
the results of recent meta-analyses of available clinical trials,
which demonstrated that, when taken together, exogenous
OT administrations did not improve symptoms of psychiatric disorders with the exception of autism spectrum
disorder, although weak to moderate benecial effects were
found for healthy controls (Bakermans-Kranenburg and van
IJzendoorn, 2013). While meta-analytic results are discouraging, more research is necessary given that the number of
clinical trials available for the meta-analyses were small for
many psychiatric conditions.

5.4.

Can exogenous oxytocin benet the treatment of

postpartum depression?

While data from animal models suggest that OT may have

potential in the treatment of PPD, the future of exogenous OT
in human psychiatric disorders remains unclear. To date,
limited data exist on the antidepressant or anxiolytic effects
of exogenous OT in women, and a small number of available
studies have demonstrated null (Rupp et al., 2012) or negative
results (Domes et al., 2010; Mah et al., 2013). The role of
exogenous OT in human mothering has received more direct
support (Riem et al., 2011, 2012), although growing evidence
suggests that its effects are critically moderated by women's
early caregiving experiences (Bakermans-Kranenburg et al.,
2012). While we are cautiously optimistic about OT's therapeutic potential, we believe that there are many questions
that remain to be answered. Here, we highlight some of these
remaining questions for future research.
First, it would be of great importance to identify individual
differences among PPD patients that may moderate the effects
of exogenous OT. PPD patients are likely a heterogeneous
group of individuals demonstrating a large variability in OT
receptor function, endogenous OT production, and early caregiving experiences. As these factors are understood to alter
one's responsivity to exogenous OT, careful investigation of
these intraindividual characteristics and identication of relevant neurobiological and behavioral markers are of paramount
interest. Given the pattern of results reviewed, it is possible
that exogenous OT may yield benecial effects only in a
subgroup of PPD patients. Such results may not be apparent
and may even be obscured in between-group designs, where
effects are averaged across individuals and within-group

226

brain research 1580 (2014) 219232

individual differences are overlooked (Guastella and MacLeod,

2012). We concur with others (e.g., Guastella and MacLeod, 2012)
that the imperative next step in OT translational research is to
develop cognitive, behavioral, and neurobiological markers that
can index the degree to which patients may be responsive to
exogenous administrations of OT.
Second, gender is an important consideration given the
differences in the endogenous OT levels between men and
women. Furthermore, gonadal hormones, estrogen in particular, are understood to be critically involved in the regulation of OT, whether endogenously produced or exogenously
administered. It is in this regard that a relative dearth of
clinical trials in women is particularly problematic. It is not
yet clear to what degree the extant ndings obtained in men
can be generalized to women, and particularly to postpartum
women who undergo signicant hormonal changes. It is also
unclear how, and to what extent, menstrual cycle and
accompanying uctuations in gonadal hormones moderate
the effects of exogenously administered OT and contribute to
divergent results (e.g., see Domes et al., 2010 vs. Rupp et al.,
2012). It is important that future studies recruit female
participants, and specically postpartum women, to examine
the effects of OT in this unique population.
Third, for therapeutic use of exogenous OT, it would be
important to systematically address questions of dosage,
timing, and side effects associated with long-term administration. All clinical trials to date have used low doses (18 to
40 IU) for a short span of time, with minimal reported side
effects (MacDonald et al., 2011). Future research should
examine the safety of high-dose long-term use of OT. It
would be critical to understand how chronic exogenous
administrations of OT may affect endogenous OT production
as well as complex neuroendocrine functions in the postpartum period.
Fourth, it remains to be determined whether exogenous
OT should be used as a stand-alone treatment or should
better be integrated with other therapies. Most available
clinical trials have excluded patients undergoing medication
treatment, and there is currently limited data from which to
draw conclusions about the safety and efcacy of OT as an
augmentation agent (MacDonald et al., 2011). Furthermore,
anxiolytic and prosocial effects of OT have led some to
believe that exogenous OT administrations may help aid
the process of psychotherapy. This would be a fruitful area
for future investigation.

6.

Conclusions

While OT initially appeared to offer much promise, the

pattern of results that has thus far emerged is more nuanced
and inconsistent than it appeared to be at rst. The literature
reviewed in preceding sections suggest that studies are
beginning to shed light upon the complex context- and
person-dependent nature of OT effects. We propose that
future studies attend to individual variations that may be
present among mothers with PPD, rather than looking for
the uniform effect across all mothers. We underscore that
focused studies that tease apart OT-related individual

variations are necessary to fully evaluate the therapeutic

potential of OT in the treatment of PPD.

Funding sources
This work was supported by the Eunice Kennedy Shriver
National Institute of Child Health and Human Development
[R01HD065819]; and the National Institute on Drug Abuse
[R01DA026437]. The content is solely the responsibility of the
authors and does not necessarily represent the ofcial views
of these institutes or the National Institutes of Health.

r e f e r e n c e s

Abou-Saleh, M.T., et al., 1998. Hormonal aspects of postpartum

depression. Psychoneuroendocrinology 23, 465475.
Ahokas, A., et al., 2001. Estrogen deficiency in severe postpartum
depression: successful treatment with sublingual physiologic
17beta-estradiol: a preliminary study. J. Clin. Psychiatry 62,
332336.
Alpern, L., Lyons-Ruth, K., 1993. Preschool children at social risk:
chronicity and timing of maternal depressive symptoms and
child behavior problems at school and at home. Dev.
Psychopathol 5, 371387.
Altemus, M., et al., 1995. Suppression of hypothalmicpituitary
adrenal axis responses to stress in lactating women. J. Clin.
Endocrinol. Metab 80, 29542959.
American Psychiatric Association, 2000. Diagnostic and
Statistical Manual of Mental Disorders, fourth ed. American
Psychiatric Association, Washington, DC (text rev.).
American Psychiatric Association, 2013. Diagnostic and
Statistical Manual of Mental Disorders, fifth ed. American
Psychiatric Publishing, Arlington, VA.
Amico, J.A., Johnston, J.M., Vagnucci, A.H., 1994. Suckling-induced
attenuation of plasma cortisol concentrations in postpartum
lactating women. Endocrine Res. 20, 7987.
Amico, J.A., et al., 2008. Oxytocin knockout mice: a model for
studying stress-related and ingestive behaviours. Prog. Brain
Res. 170, 5364.
Anagnostou, E., et al., 2012. Intranasal oxytocin versus placebo in
the treatment of adults with autism spectrum disorders: a
randomized controlled trial. Mol. Autism 3, 16.
Andari, E., et al., 2010. Promoting social behavior with oxytocin in
high-functioning autism spectrum disorders. Proc. Nat. Acad.
Sci. U.S.A. 107, 43894394.
Appleby, L., et al., 1997. A controlled study of fluoxetine and
cognitive-behavioural counselling in the treatment of
postnatal depression. BMJ 314, 932936.
Apter-Levy, Y., et al., 2013. Impact of maternal depression across
the first 6 years of life on the childs mental health, social
engagement, and empathy: the moderating role of oxytocin.
Am. J. Psychiatry 170, 11611168.
Arletti, R., Bertolini, A., 1987. Oxytocin acts as an antidepressant
in two animal models of depression. Life Sci. 41, 17251730.
Atzil, S., Hendler, T., Feldman, R., 2011. Specifying the
neurobiological basis of human attachment: brain, hormones,
and behavior in synchronous and intrusive mothers.
Neuropsychopharmacology 36, 26032615.
Averbeck, B.B., et al., 2012. Emotion recognition and oxytocin in
patients with schizophrenia. Psychol. Med. 42, 259266.
Azak, S., Raeder, S., 2013. Trajectories of parenting behavior and
maternal depression. Infant Behav. Dev 36, 391402.
Bakermans-Kranenburg, M.J., et al., 2012. Oxytocin decreases
handgrip force in reaction to infant crying in females without

brain research 1580 (2014) 219232

harsh parenting experiences. Soc. Cogn. Affect Neurosci 7,

951957.
Bakermans-Kranenburg, M.J., van IJzendoorn, M.H., 2013. Sniffing
around oxytocin: review and meta-analyses of trials in
healthy and clinical groups with implications for
pharmacotherapy. Transl. Psychiatry 3, e258.
Bartz, J., et al., 2011a. Oxytocin can hinder trust and cooperation
in borderline personality disorder. Soc. Cogn. Affect. Neurosci
6, 556563.
Bartz, J.A., Hollander, E., 2006. The neuroscience of affiliation:
forging links between basic and clinical research on
neuropeptides and social behavior. Horm. Behav 50, 518528.
Bartz, J.A., et al., 2011b. Social effects of oxytocin in humans:
context and person matter. Trends Cogn. Sci 15, 301309.
Beck, C.T., 2001. Predictors of postpartum depression: an update.
Nurs. Res. 50, 275285.
Beck, C.T., 2006. Postpartum depression: it isnt just the blues.
Am. J. Nurs. 106, 4050.
Benarroch, E.E., 2013. Oxytocin and vasopressin: social
neuropeptides with complex neuromodulatory functions.
Neurology 80, 15211528.
Bennett, H.A., et al., 2004. Depression during pregnancy: overview
of clinical factors. Clin. Drug Investig 24, 157179.
Bledsoe, S.E., Grote, N.K., 2006. Treating depression during
pregnancy and the postpartum: a preliminary meta-analysis.
Res. Social Work Pract. 16, 109120.
Bloch, M., et al., 2000. Effects of gonadal steroids in women with a
history of postpartum depression. Am. J. Psychiatry 157,
924930.
Bloch, M., et al., 2005. Risk factors associated with the
development of postpartum mood disorders. J. Affect.
Disorders 88, 918.
Bloch, M., et al., 2012. The effect of sertraline add-on to brief
dynamic psychotherapy for the treatment of postpartum
depression: a randomized, double-blind, placebo-controlled
study. J. Clin. Psychiatry 73, 235241.
Blom, E.A., et al., 2010. Perinatal complications increase the risk
of postpartum depression. The generation R study. BJOG 117,
13901398.
Buttner, M.M., OHara, M.W., Watson, D., 2012. The structure of
womens mood in the early postpartum. Assessment 19,
247256.
Chabrol, H., et al., 2002. Prevention and treatment of post-partum
depression: a controlled randomized study on women at risk.
Psychol. Med. 32, 10391047.
Chabrol, H., et al., 2004. Acceptability of psychotherapy and
antidepressants for postnatal depression among newly
delivered mothers. J. Reprod. Infant Psychol. 22, 512.
Champagne, F., et al., 2001. Naturally occurring variations in
maternal behavior in the rat are associated with differences in
estrogen-inducible central oxytocin receptors. Proc. Natl.
Acad. Sci. USA 98, 1273612741.
Champagne, F.A., et al., 2003a. Variations in maternal care in the
rat as a mediating influence for the effects of environment on
development. Physiol. Behav. 79, 359371.
Champagne, F.A., et al., 2003b. Natural variations in maternal
care are associated with estrogen receptor alpha expression
and estrogen sensitivity in the medial preoptic area.
Endocrinology 144, 47204724.
Champagne, F.A., et al., 2004. Variations in nucleus accumbens
dopamine associated with individual differences in maternal
behavior in the rat. J. Neurosci. 24, 41134123.
Champagne, F.A., et al., 2006. Maternal care associated with
methylation of the estrogen receptor-alpha1b promoter and
estrogen receptor-alpha expression in the medial preoptic
area of female offspring. Endocrinology 147, 29092915.

227

Champagne, F.A., 2008. Epigenetic mechanisms and the

transgenerational effects of maternal care. Front.
Neuroendocrinol. 29, 386397.
Chiodera, P., et al., 1991. Relationship between plasma profiles of
oxytocin and adrenocorticotropic hormone during suckling or
breast stimulation in women. Horm. Res. 35, 119123.
Cicchetti, D., Rogosch, F.A., Toth, S.L., 2000. The efficacy of
toddler-parent psychotherapy for fostering cognitive
development in offspring of depressed mothers. J. Abnorm.
Child Psychol. 28, 135148.
Cipriani, A., et al., 2007. Metareview on short-term effectiveness
and safety of antidepressants for depression: an evidencebased approach to inform clinical practice. Can. J. Psychiatry
52, 553562.
Clark, R., Tluczek, A., Wenzel, A., 2003. Psychotherapy for
postpartum depression: a preliminary report. Am. J.
Orthopsychiatry 73, 441454.
Cooper, P.J., et al., 2003. Controlled trial of the short- and longterm effect of psychological treatment of post-partum
depression. I. Impact on maternal mood. Br. J. Psychiatry 182,
412419.
Corwin, E.J., et al., 2010. The heritability of postpartum
depression. Biol. Res. Nurs. 12, 7383.
Cuijpers, P., Brannmark, J.G., van Straten, A., 2008. Psychological
treatment of postpartum depression: a meta-analysis. J. Clin.
Psychol. 64, 103118.
Cyranowski, J.M., et al., 2008. Evidence of dysregulated peripheral
oxytocin release among depressed women. Psychosom. Med.
70, 967975.
Dawes, M., Chowienczyk, P.J., 2001. Drugs in pregnancy.
Pharmacokinetics in pregnancy. Best Pract. Res. Clin. Obstet.
Gynaecol 15, 819826.
Dawson, G., et al., 2003. Preschool outcomes of children of
depressed mothers: role of maternal behavior, contextual risk,
and childrens brain activity. Child Dev. 74, 11581175.
De Crescenzo, F., et al., 2013. Selective serotonin reuptake
inhibitors (SSRIs) for post-partum depression (PPD): a
systematic review of randomized clinical trials. J. Affect.
Disorders, http://dxdoi.org/10.1016/j.jad.2013.09.019.
De Dreu, C.K., et al., 2010. The neuropeptide oxytocin regulates
parochial altruism in intergroup conflict among humans.
Science 328, 14081411.
De Dreu, C.K., et al., 2012. Oxytocin modulates selection of allies
in intergroup conflict. Proc. Biol. Sci 279, 11501154.
Demitrack, M.A., Gold, P.W., 1988. Oxytocin: neurobiologic
considerations and their implications for affective illness.
Prog. Neuro-Psychopharmacol. Biol. Psychiatry 12 (Suppl.),
S2351.
Dennis, C.L., Janssen, P.A., Singer, J., 2004. Identifying women atrisk for postpartum depression in the immediate postpartum
period. Acta Psychiatr. Scand. 110, 338346.
Dennis, C.L., Hodnett, E., 2007. Psychosocial and psychological
interventions for treating postpartum depression. Cochrane
Database Syst. Rev (CD006116).
Dennis, C.L., McQueen, K., 2007. Does maternal postpartum
depressive symptomatology influence infant feeding
outcomes?. Acta Paediatr 96, 590594.
Dennis, C.L., Ross, L.E., Herxheimer, A., 2008. Oestrogens and
progestins for preventing and treating postpartum depression.
Cochrane Database Syst. Rev (CD001690).
Dennis, C.L., McQueen, K., 2009. The relationship between infantfeeding outcomes and postpartum depression: a qualitative
systematic review. Pediatrics 123, e736e751.
Ditzen, B., et al., 2009. Intranasal oxytocin increases positive
communication and reduces cortisol levels during couple
conflict. Biol. Psychiatry 65, 728731.

228

brain research 1580 (2014) 219232

Domes, G., et al., 2010. Effects of intranasal oxytocin on

emotional face processing in women.
Psychoneuroendocrinology 35, 8393.
Doornbos, B., et al., 2009. The development of peripartum
depressive symptoms is associated with gene polymorphisms
of MAOA, 5-HTT and COMT. Prog. Neuro-Psychopharmacol.
Biol. Psychiatry 33, 12501254.
Ebner, K., et al., 2000. A single social defeat experience selectively
stimulates the release of oxytocin, but not vasopressin, within
the septal brain area of male rats. Brain Res. 872, 8792.
Ebner, K., et al., 2005. Release of oxytocin in the rat central
amygdala modulates stress-coping behavior and the release of
excitatory amino acids. Neuropsychopharmacology 30, 223230.
Ellfolk, M., Malm, H., 2010. Risks associated with in utero and
lactation exposure to selective serotonin reuptake inhibitors
(SSRIs). Reprod. Toxicol 30, 249260.
Elliott, S., 2000. Report on the Satra Bruk workshop on
classification of postnatal mental disorders. Arch. Womens
Ment. Health 3, 2733.
Emiliano, A., et al., 2007. The interface of oxytocin-labeled cells
and serotonin transporter-containing fibers in the primate
hypothalamus: a substrate for SSRIs therapeutic effects?.
Neuropsychopharmacology 32, 977988.
Engelmann, M., Landgraf, R., Wotjak, C.T., 2004. The
hypothalamic-neurohypophysial system regulates the
hypothalamicpituitaryadrenal axis under stress: an old
concept revisited. Front. Neuroendocrinol 25, 132149.
Epperson, C.N., McDougle, C.J., Price, L.H., 1996. Intranasal
oxytocin in obsessivecompulsive disorder. Biol. Psychiatry 40,
547549.
Epperson, C.N., et al., 2003. Maternal fluoxetine treatment in the
postpartum period: effects on platelet serotonin and plasma
drug levels in breastfeeding mother-infant pairs. Pediatrics
112, e425.
Feifel, D., et al., 2010. Adjunctive intranasal oxytocin reduces
symptoms in schizophrenia patients. Biol. Psychiatry 68,
678680.
Feldman, R., 2007. Maternal versus child risk and the
development of parentchild and family relationships in five
high-risk populations. Dev. Psychopathol 19, 293312.
Feldman, R., et al., 2007. Evidence for a neuroendocrinological
foundation of human affiliation: plasma oxytocin levels
across pregnancy and the postpartum period predict mother
infant bonding. Psychol. Sci 18, 965970.
Feldman, R., et al., 2010a. Natural variations in maternal and
paternal care are associated with systematic changes in
oxytocin following parentinfant contact.
Psychoneuroendocrinology 35, 11331141.
Feldman, R., Gordon, I., Zagoory-Sharon, O., 2010b. The crossgeneration transmission of oxytocin in humans. Horm. Behav.
58, 669676.
Feldman, R., Gordon, I., Zagoory-Sharon, O., 2011. Maternal and
paternal plasma, salivary, and urinary oxytocin and parentinfant synchrony: considering stress and affiliation
components of human bonding. Dev. Sci 14, 752761.
Field, T., 2010. Postpartum depression effects on early
interactions, parenting, and safety practices: a review. Infant
Behav. Dev 33, 16.
Fitelson, E., et al., 2010. Treatment of postpartum depression:
clinical, psychological and pharmacological options. Int. J.
Womens Health 3, 114.
Flynn, H.A., et al., 2004. Rates of maternal depression in pediatric
emergency department and relationship to child service
utilization. Gen. Hospital Psychiatry 26, 316322.
Forman, D.R., et al., 2007. Effective treatment for postpartum
depression is not sufficient to improve the developing
motherchild relationship. Dev. Psychopathol 19, 585602.

Forty, L., et al., 2006. Familiality of postpartum depression in

unipolar disorder: results of a family study. Am. J. Psychiatry
163, 15491553.
Francis, D., et al., 1999. Nongenomic transmission across
generations of maternal behavior and stress responses in the
rat. Science 286, 11551158.
Francis, D.D., Champagne, F.C., Meaney, M.J., 2000. Variations in
maternal behaviour are associated with differences in
oxytocin receptor levels in the rat. J. Neuroendocrinol. 12,
11451148.
Frasch, A., et al., 1995. Reduction of plasma oxytocin levels in
patients suffering from major depression. Adv. Exp. Med. Biol
395, 257258.
Gavin, N.I., et al., 2005. Perinatal depression: a systematic review
of prevalence and incidence. Obstetr. Gynecol 106, 10711083.
Gaynes, B.N., et al., 2005. Perinatal Depression: Prevalence,
Screening Accuracy, and Screening Outcomes. Evidence
Report/Technology Assessment No. 119 (Prepared by the RTIUniversity of North Carolina Evidence-based Practice Center,
under Contract No. 290-02-0016.) AHRQ Publication
No. 05-E006-2.
Gimpl, G., Fahrenholz, F., 2001. The oxytocin receptor system:
structure, function, and regulation. Physiol. Rev. 81, 629683.
Gordon, I., et al., 2008. Oxytocin and cortisol in romantically
unattached young adults: associations with bonding and
psychological distress. Psychophysiology 45, 349352.
Gordon, I., et al., 2010a. Oxytocin, cortisol, and triadic family
interactions. Physiol. Behav. 101, 679684.
Gordon, I., et al., 2010b. Oxytocin and the development of
parenting in humans. Biol. Psychiatry 68, 377382.
Gregoire, A.J., et al., 1996. Transdermal oestrogen for treatment of
severe postnatal depression. Lancet 347, 930933.
Groer, M.W., Morgan, K., 2007. Immune, health and endocrine
characteristics of depressed postpartum mothers.
Psychoneuroendocrinology 32, 133139.
Grote, N.K., et al., 2009. A randomized controlled trial of culturally
relevant, brief interpersonal psychotherapy for perinatal
depression. Psychiatr. Serv. 60, 313321.
Guastella, A.J., et al., 2009. A randomized controlled trial of
intranasal oxytocin as an adjunct to exposure therapy for social
anxiety disorder. Psychoneuroendocrinology 34, 917923.
Guastella, A.J., et al., 2010. Intranasal oxytocin improves emotion
recognition for youth with autism spectrum disorders. Biol.
Psychiatry 67, 692694.
Guastella, A.J., MacLeod, C., 2012. A critical review of the
influence of oxytocin nasal spray on social cognition in
humans: evidence and future directions. Horm. Behav. 61,
410418.
Harris, B., et al., 1996. Cardiff puerperal mood and hormone
study. III. Postnatal depression at 5 to 6 weeks postpartum,
and its hormonal correlates across the peripartum period.
Br. J. Psychiatry 168, 739744.
Hay, D.F., et al., 2001. Intellectual problems shown by 11-year-old
children whose mothers had postnatal depression. J. Child
Psychol. Psychiatry Allied Disciplines 42, 871889.
Heim, C., et al., 2009. Lower CSF oxytocin concentrations in women
with a history of childhood abuse. Mol. Psychiatry 14, 954958.
Heinrichs, M., et al., 2001. Effects of suckling on hypothalamic
pituitaryadrenal axis responses to psychosocial stress in
postpartum lactating women. J. Clin. Endocrinol. Metab. 86,
47984804.
Heinrichs, M., et al., 2003. Social support and oxytocin interact to
suppress cortisol and subjective responses to psychosocial
stress. Biol. Psychiatry 54, 13891398.
Hendrick, V., et al., 2000. Postpartum and nonpostpartum
depression: differences in presentation and response to
pharmacologic treatment. Depress Anxiety 11, 6672.

brain research 1580 (2014) 219232

Hinshaw, K., et al., 2008. A randomised controlled trial of early

versus delayed oxytocin augmentation to treat primary
dysfunctional labour in nulliparous women. BJOG 115,
12891295.
Hurlemann, R., et al., 2010. Oxytocin enhances amygdaladependent, socially reinforced learning and emotional
empathy in humans. J. Neurosci 30, 49995007.
Insel, T.R., Harbaugh, C.R., 1989. Lesions of the hypothalamic
paraventricular nucleus disrupt the initiation of maternal
behavior. Physiol. Behav 45, 10331041.
Insel, T.R., 2010. The challenge of translation in social
neuroscience: a review of oxytocin, vasopressin, and affiliative
behavior. Neuron 65, 768779.
Jameson, P.B., et al., 1997. Mother-toddler interaction patterns
associated with maternal depression. Dev. Psychopathol 9,
537550.
Javed, A., et al., 1999. D-Fenfluramine induces serotonin-mediated
Fos expression in corticotropin-releasing factor and oxytocin
neurons of the hypothalamus, and serotonin-independent Fos
expression in enkephalin and neurotensin neurons of the
amygdala. Neuroscience 90, 851858.
Jolley, S.N., et al., 2007. Dysregulation of the hypothalamic
pituitaryadrenal axis in postpartum depression. Biol. Res.
Nurs 8, 210222.
Kammerer, M., Taylor, A., Glover, V., 2006. The HPA axis and
perinatal depression: a hypothesis. Arch. Womens Ment.
Health 9, 187196.
Kendell, R.E., Chalmers, J.C., Platz, C., 1987. Epidemiology of
puerperal psychoses. Br. J. Psychiatry 150, 662673.
Kendrick, K.M., Keverne, E.B., Baldwin, B.A., 1987.
Intracerebroventricular oxytocin stimulates maternal
behaviour in the sheep. Neuroendocrinology 46, 5661.
Keverne, E.B., Kendrick, K.M., 1992. Oxytocin facilitation of
maternal behavior in sheep. Ann. N. Y. Acad. Sci 652, 83101.
Kim, D.R., OReardon, J.P., Epperson, C.N., 2010. Guidelines for the
management of depression during pregnancy. Curr. Psychiatry
Rep. 12, 279281.
Kim, P., et al., 2011. Breastfeeding, brain activation to own infant
cry, and maternal sensitivity. J. Child Psychol. Psychiatry
Allied Disciplines 52, 907915.
Kim, S., et al., 2014. Maternal oxytocin response predicts mother-toinfant gaze. Brain Res. 1580, 133142, http://dx.doi.org/10.1016/j.
brainres.2013.10.050.
Kirsch, I., et al., 2008. Initial severity and antidepressant benefits:
a meta-analysis of data submitted to the Food and Drug
Administration. PLoS Med 5, e45.
Kirsch, P., et al., 2005. Oxytocin modulates neural circuitry for
social cognition and fear in humans. J. Neurosci 25,
1148911493.
Klier, C.M., et al., 2007. The role of estrogen and progesterone in
depression after birth. J. Psychiatr. Res 41, 273279.
Kosfeld, M., et al., 2005. Oxytocin increases trust in humans.
Nature 435, 673676.
Labuschagne, I., et al., 2010. Oxytocin attenuates amygdala
reactivity to fear in generalized social anxiety disorder.
Neuropsychopharmacology 35, 24032413.
Lancel, M., Kromer, S., Neumann, I.D., 2003. Intracerebral
oxytocin modulates sleep-wake behaviour in male rats. Regul.
Pept 114, 145152.
Laurent, H.K., Ablow, J.C., 2013. A face a mother could love:
depression-related maternal neural responses to infant
emotion faces. Soc. Neurosci 8, 228239.
Li, L., et al., 1999. Regulation of maternal behavior and offspring
growth by paternally expressed Peg3. Science 284, 330333.
Liberzon, I., et al., 1997. Motivational properties of oxytocin
in the conditioned place preference paradigm.
Neuropsychopharmacology 17, 353359.

229

Lightman, S.L., et al., 2001. Peripartum plasticity within the

hypothalamopituitaryadrenal axis. Prog. Brain Res 133,
111129.
Lischke, A., et al., 2012. Intranasal oxytocin enhances emotion
recognition from dynamic facial expressions and leaves eyegaze unaffected. Psychoneuroendocrinology 37, 475481.
Logsdon, M.C., Wisner, K., Hanusa, B.H., 2009. Does maternal role
functioning improve with antidepressant treatment in women
with postpartum depression?. J. Womens Health (Larchmt) 18,
8590.
Logsdon, M.C., et al., 2011. Depression treatment and maternal
functioning. Depress. Anxiety 28, 10201026.
Lommatzsch, M., et al., 2006. Maternal serum concentrations of
BDNF and depression in the perinatal period.
Psychoneuroendocrinology 31, 388394.
Lovejoy, M.C., et al., 2000. Maternal depression and parenting
behavior: a meta-analytic review. Clin. Psychol. Rev. 20,
561592.
Lumley, J., Austin, M.P., Mitchell, C., 2004. Intervening to reduce
depression after birth: a systematic review of the randomized
trials. Int. J. Technol. Assess. Health Care 20, 128144.
MacDonald, E., et al., 2011. A review of safety, side-effects and
subjective reactions to intranasal oxytocin in human
research. Psychoneuroendocrinology 36, 11141126.
Macdonald, K., Macdonald, T.M., 2010. The peptide that binds: a
systematic review of oxytocin and its prosocial effects in
humans. Harvard Rev. Psychiatry 18, 121.
Mah, B.L., et al., 2013. Oxytocin in postnatally depressed mothers:
its influence on mood and expressed emotion. Prog. NeuroPsychopharmacol. Biol. Psychiatry 40, 267272.
Malphurs, J.E., et al., 1996. Touch by intrusive and withdrawn
mothers with depressive symptoms. Early Dev. Parenting 5,
111115.
McCarthy, M.M., 1990. Oxytocin inhibits infanticide in
female house mice (Mus domesticus). Horm. Behav 24,
365375.
McLearn, K.T., et al., 2006. Maternal depressive symptoms at 2 to
4 months post partum and early parenting practices. Arch.
Pediatr. Adolescent Med 160, 279284.
Meaney, M.J., 2001. Maternal care, gene expression, and the
transmission of individual differences in stress reactivity
across generations. Ann. Rev. Neurosci 24, 11611192.
Meinlschmidt, G., Heim, C., 2007. Sensitivity to intranasal
oxytocin in adult men with early parental separation. Biol.
Psychiatry 61, 11091111.
Melis, M.R., et al., 2007. Oxytocin injected into the ventral
tegmental area induces penile erection and increases
extracellular dopamine in the nucleus accumbens and
paraventricular nucleus of the hypothalamus of male rats.
Eur. J. Neurosci 26, 10261035.
Meyer-Lindenberg, A., et al., 2011. Oxytocin and vasopressin in
the human brain: social neuropeptides for translational
medicine. Nat. Rev. Neurosci 12, 524538.
Milgrom, J., et al., 2005. A randomized controlled trial of
psychological interventions for postnatal depression. Br. J.
Clin. Psychol 44, 529542.
Mills-Koonce, W.R., et al., 2008. Changes in maternal sensitivity
across the first three years: are mothers from different
attachment dyads differentially influenced by depressive
symptomatology?. Attach. Hum. Dev 10, 299317.
Misri, S., et al., 2004. Restoration of functionality in postpartum
depressed mothers: an open-label study with escitalopram.
J. Clin. Psychopharmacol 32, 729732.
Modabbernia, A., et al., 2013. Intranasal oxytocin as an adjunct to
risperidone in patients with schizophrenia: an 8-week,
randomized, double-blind, placebo-controlled study. CNS
Drugs 27, 5765.

230

brain research 1580 (2014) 219232

Moses-Kolko, E.L., et al., 2009. Transdermal estradiol for

postpartum depression: a promising treatment option. Clin.
Obstetr. Gynecol 52, 516529.
Mulcahy, R., et al., 2010. A randomised control trial for the
effectiveness of group Interpersonal Psychotherapy for
postnatal depression. Arch. Womens Ment. Health 13, 125139.
Munk-Olsen, T., et al., 2006. New parents and mental disorders: a
population-based register study. JAMA 296, 25822589.
Murphy-Eberenz, K., et al., 2006. Is perinatal depression familial?.
J. Affect. Disorders 90, 4955.
Murray, L., Cooper, P.J., 1997. Postpartum depression and child
development. Psychol. Med. 27, 253260.
Murray, L., et al., 2003. Controlled trial of the short- and long-term
effect of psychological treatment of post-partum depression:
2. Impact on the motherchild relationship and child
outcome. Br. J. Psychiatry 182, 420427.
Murray, L., et al., 2011. Maternal postnatal depression and the
development of depression in offspring up to 16 years of age.
J. Am. Acad. Child Adolescent Psychiatry 50, 460470.
Neumann, I.D., Torner, L., Wigger, A., 2000. Brain oxytocin:
differential inhibition of neuroendocrine stress responses and
anxiety-related behaviour in virgin, pregnant and lactating
rats. Neuroscience 95, 567575.
Neumann, I.D., 2003. Brain mechanisms underlying emotional
alterations in the peripartum period in rats. Depress. Anxiety
17, 111121.
Neumann, I.D., Landgraf, R., 2012. Balance of brain oxytocin and
vasopressin: implications for anxiety, depression, and social
behaviors. Trends Neurosci. 35, 649659.
NICHD Early Child Care Research Network, 1999. Chronicity of
maternal depressive symptoms, maternal sensitivity, and
child functioning at 36 months.. Dev. Psychol. 35, 1297-1310.
Nishioka, T., et al., 1998. Stress increases oxytocin release within
the hypothalamic paraventricular nucleus. Brain Res 781,
5761.
Nomura, M., et al., 2003. Enhanced up-regulation of corticotropinreleasing hormone gene expression in response to restraint
stress in the hypothalamic paraventricular nucleus of
oxytocin gene-deficient male mice. J. Neuroendocrinol 15,
10541061.
Nowakowska, E., et al., 2002. Role of neuropeptides in
antidepressant and memory improving effects of venlafaxine.
Pol. J. Pharmacol 54, 605613.
Numan, M., Smith, H.G., 1984. Maternal behavior in rats: evidence
for the involvement of preoptic projections to the ventral
tegmental area. Behav. Neurosci 98, 712727.
OHara, M.W., Swain, A.M., 1996. Rates and risk of postpartum
depressiona meta-analysis. Int. Rev. Psychiatry 8, 3754.
OHara, M.W., et al., 2000. Efficacy of interpersonal psychotherapy
for postpartum depression. Arch. Gen. Psychiatry 57,
10391045.
OHara, M.W., McCabe, J.E., 2013. Postpartum depression: current
status and future directions. Annu. Rev. Clin. Psychol. 9,
379407.
Okano, T., Nomura, J., 1992. Endocrine study of the maternity
blues. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 16,
921932.
Olazabal, D.E., Young, L.J., 2006. Species and individual
differences in juvenile female alloparental care are associated
with oxytocin receptor density in the striatum and the lateral
septum. Horm. Behav. 49, 681687.
Ozsoy, S., Esel, E., Kula, M., 2009. Serum oxytocin levels in
patients with depression and the effects of gender and
antidepressant treatment. Psychiatry Res 169, 249252.
Pang, W.W., Hartmann, P.E., 2007. Initiation of human lactation:
secretory differentiation and secretory activation. J. Mammary
Gland Biol. Neoplasia 12, 211221.

Paulson, J.F., Dauber, S., Leiferman, J.A., 2006. Individual and

combined effects of postpartum depression in mothers and
fathers on parenting behavior. Pediatrics 118, 659668.
Payne, J.L., et al., 2008. Familial aggregation of postpartum mood
symptoms in bipolar disorder pedigrees. Bipolar Disord 10,
3844.
Pearlstein, T.B., et al., 2006. Patient choice of treatment for
postpartum depression: a pilot study. Arch. Womens Ment.
Health 9, 303308.
Pedersen, C.A., Prange Jr., A.J., 1979. Induction of maternal
behavior in virgin rats after intracerebroventricular
administration of oxytocin. Proc. Nat. Acad. Sci. U.S.A 76,
66616665.
Pedersen, C.A., et al., 1982. Oxytocin induces maternal behavior
in virgin female rats. Science 216, 648650.
Pedersen, C.A., et al., 1994. Oxytocin activates the postpartum
onset of rat maternal behavior in the ventral tegmental and
medial preoptic areas. Behav. Neurosci 108, 11631171.
Pedersen, C.A., et al., 2011. Intranasal oxytocin reduces psychotic
symptoms and improves Theory of Mind and social
perception in schizophrenia. Schizophrenia Res 132, 5053.
Perry, A., et al., 2013. Face or body? Oxytocin improves perception
of emotions from facial expressions in incongruent emotional
body context. Psychoneuroendocrinology 38, 28202825.
Pincus, D., et al., 2010. Inverse effects of oxytocin on attributing
mental activity to others in depressed and healthy subjects: a
double-blind placebo controlled FMRI study. Front. Psychiatry
1, 134.
Pitman, R.K., Orr, S.P., Lasko, N.B., 1993. Effects of intranasal
vasopressin and oxytocin on physiologic responding during
personal combat imagery in Vietnam veterans with
posttraumatic stress disorder. Psychiatry Res 48, 107117.
Pitts, A.F., et al., 1995. Cerebrospinal fluid corticotropin-releasing
hormone, vasopressin, and oxytocin concentrations in treated
patients with major depression and controls. Biol. Psychiatry
38, 330335.
Poobalan, A.S., et al., 2007. Effects of treating postnatal
depression on mother-infant interaction and child
development: systematic review. Br. J. Psychiatry 191,
378386.
Ragnauth, A.K., et al., 2005. Female oxytocin gene-knockout mice,
in a semi-natural environment, display exaggerated
aggressive behavior. Genes Brain Behav 4, 229239.
Riem, M.M., et al., 2011. Oxytocin modulates amygdala, insula,
and inferior frontal gyrus responses to infant crying: a
randomized controlled trial. Biol. Psychiatry 70, 291297.
Riem, M.M., et al., 2012. No laughing matter: intranasal oxytocin
administration changes functional brain connectivity during
exposure to infant laughter. Neuropsychopharmacology 37,
12571266.
Riem, M.M., et al., 2013. Does intranasal oxytocin promote
prosocial behavior to an excluded fellow player? A
randomized-controlled trial with Cyberball.
Psychoneuroendocrinology 38, 14181425.
Ring, R.H., et al., 2010. Receptor and behavioral pharmacology of
WAY-267464, a non-peptide oxytocin receptor agonist.
Neuropharmacology 58, 6977.
Robertson, E., et al., 2004. Antenatal risk factors for postpartum
depression: a synthesis of recent literature. Gen. Hospital
Psychiatry 26, 289295.
Rodrigues, S.M., et al., 2009. Oxytocin receptor genetic variation
relates to empathy and stress reactivity in humans. Proc. Nat.
Acad. Sci. U.S.A. 106, 2143721441.
Ross, H.E., et al., 2009a. Characterization of the oxytocin system
regulating affiliative behavior in female prairie voles.
Neuroscience 162, 892903.
Ross, H.E., et al., 2009b. Variation in oxytocin receptor density in
the nucleus accumbens has differential effects on affiliative

brain research 1580 (2014) 219232

behaviors in monogamous and polygamous voles. J. Neurosci

29, 13121318.
Ross, H.E., Young, L.J., 2009. Oxytocin and the neural mechanisms
regulating social cognition and affiliative behavior. Front.
Neuroendocrinol. 30, 534547.
Ross, L.E., et al., 2003. Measurement issues in postpartum
depression Part 1: Anxiety as a feature of postpartum
depression. Arch. Womens Ment. Health 6, 5157.
Rupp, H.A., et al., 2012. Amygdala response to negative images in
postpartum vs nulliparous women and intranasal oxytocin.
Soc. Cogn. Affect Neurosci http://dx.doi.org/10.1093/scan/
nss100.
Sanjuan, J., et al., 2008. Mood changes after delivery: role of the
serotonin transporter gene. Br. J. Psychiatry 193, 383388.
Scantamburlo, G., et al., 2007. Plasma oxytocin levels and anxiety
in patients with major depression. Psychoneuroendocrinology
32, 407410.
Schneiderman, I., et al., 2012. Oxytocin during the initial stages of
romantic attachment: relations to couples interactive
reciprocity. Psychoneuroendocrinology 37, 12771285.
Schwartz, C.E., et al., 1990. Maternal expressed emotion and
parental affective disorder: risk for childhood depressive
disorder, substance abuse, or conduct disorder. J. Psychiatr.
Res 24, 231250.
Shahrokh, D., et al., 2010. Oxytocin-dopamine interactions
mediate variations in maternal behavior in the rat.
Endocrinology 151, 22762286.
Sharp, D.J., et al., 2010. A pragmatic randomised controlled trial to
compare antidepressants with a community-based
psychosocial intervention for the treatment of women with
postnatal depression: the RESPOND trial. Health Technol.
Assess 14, iiiiv, ixxi, 1153.
Sit, D.K., Wisner, K.L., 2009. Identification of postpartum
depression. Clin. Obstetr. Gynecol 52, 456468.
Skalkidou, A., et al., 2010. Biological aspects of postpartum
depression. Womens Health 8, 659672.
Skrundz, M., et al., 2011. Plasma oxytocin concentration during
pregnancy is associated with development of postpartum
depression. Neuropsychopharmacology 36, 18861893.
Slattery, D.A., Neumann, I.D., 2010a. Chronic icv oxytocin
attenuates the pathological high anxiety state of selectively
bred Wistar rats. Neuropharmacology 58, 5661.
Slattery, D.A., Neumann, I.D., 2010b. Oxytocin and major
depressive disorder: experimental and clinical evidence for
links to aetiology and possible treatment. Pharmaceuticals 3,
702724.
Sockol, L.E., Epperson, C.N., Barber, J.P., 2011. A meta-analysis of
treatments for perinatal depression. Clin. Psychol. Rev. 31,
839849.
Sroufe, L.A., et al., 2005. The Development of the Person. Guilford
Press, New York, NY.
Stern, D.N., 1995. The Motherhood Constellation: A Unified View
of ParentInfant Psychotherapy. Basic Books, New York, NY.
Strathearn, L., et al., 2009. Adult attachment predicts
maternal brain and oxytocin response to infant cues.
Neuropsychopharmacology 34, 26552666.
Strathearn, L., 2011. Maternal neglect: oxytocin, dopamine and
the neurobiology of attachment. J. Neuroendocrinol. 23,
10541065.
Strathearn, L., et al., 2012. Maternal oxytocin response during
motherinfant interaction: associations with adult
temperament. Horm. Behav 61, 429435.
Stuebe, A.M., et al., 2012. Failed lactation and perinatal
depression: common problems with shared neuroendocrine
mechanisms?. J. Womens Health (Larchmt) 21, 264272.
Stuebe, A.M., Grewen, K., Meltzer-Brody, S., 2013. Association
between maternal mood and oxytocin response to
breastfeeding. J. Womens Health (Larchmt) 22, 352361.

231

Sullivan, P.F., Neale, M.C., Kendler, K.S., 2000. Genetic

epidemiology of major depression: review and meta-analysis.
Am. J. Psychiatry 157, 15521562.
Takayanagi, Y., et al., 2005. Pervasive social deficits, but normal
parturition, in oxytocin receptor-deficient mice. Proc. Nat.
Acad. Sci. U.S.A. 102, 1609616101.
Taveras, E.M., et al., 2003. Clinician support and psychosocial risk
factors associated with breastfeeding discontinuation.
Pediatrics 112, 108115.
Taylor, A., et al., 2009. Diurnal pattern of cortisol output in
postnatal depression. Psychoneuroendocrinology 34,
11841188.
Treloar, S.A., et al., 1999. Genetic influences on post-natal
depressive symptoms: findings from an Australian twin
sample. Psychol. Med 29, 645654.
Tronick, E., Reck, C., 2009. Infants of depressed mothers. Harvard
Rev. Psychiatry 17, 147156.
Troutman, B.R., Cutrona, C.E., 1990. Nonpsychotic postpartum
depression among adolescent mothers. J. Abnorm. Psychol.
99, 6978.
Tu, M.T., Lupien, S.J., Walker, C.D., 2006. Diurnal salivary cortisol
levels in postpartum mothers as a function of infant feeding
choice and parity. Psychoneuroendocrinology 31,
812824.
Turner, K.M., et al., 2008. Womens views and experiences of
antidepressants as a treatment for postnatal depression: a
qualitative study. Family Pract 25, 450455.
van Ijzendoorn, M.H., et al., 2011. The impact of oxytocin
administration on charitable donating is moderated by
experiences of parental love-withdrawal. Front. Psychol 2, 258.
Van IJzendoorn, M.H., Bakermans-Kranenburg, M.J., 2012. A sniff
of trust: meta-analysis of the effects of intranasal oxytocin
administration on face recognition, trust to in-group,
and trust to out-group. Psychoneuroendocrinology 37,
438443.
van Leengoed, E., Kerker, E., Swanson, H.H., 1987. Inhibition of
post-partum maternal behaviour in the rat by injecting an
oxytocin antagonist into the cerebral ventricles. J. Endocrinol
112, 275282.
van Londen, L., et al., 1997. Plasma levels of arginine vasopressin
elevated in patients with major depression.
Neuropsychopharmacology 17, 284292.
Wang, L., et al., 2011. Prevalence and risk factors of maternal
depression during the first three years of child rearing.
J. Womens Health (Larchmt) 20, 711718.
Watkins, S., et al., 2011. Early breastfeeding experiences
and postpartum depression. Obstetr. Gynecol 118,
214221.
Weikum, W.M., et al., 2013. The impact of prenatal serotonin
reuptake inhibitor (SRI) antidepressant exposure and
maternal mood on motherinfant interactions at 3 months of
age. Infant Behav. Dev 36, 485493.
Weinberg, M.K., Tronick, E.Z., 1998. The impact of maternal
psychiatric illness on infant development. J. Clin. Psychiatry
59, 5361.
Wiklund, I., Mohlkert, P., Edman, G., 2010. Evaluation of a brief
cognitive intervention in patients with signs of postnatal
depression: a randomized controlled trial. Acta Obstet.
Gynecol. Scand 89, 11001104.
Windle, R.J., et al., 2004. Oxytocin attenuates stress-induced c-fos
mRNA expression in specific forebrain regions associated with
modulation of hypothalamopituitaryadrenal activity.
J. Neurosci 24, 29742982.
Winslow, J.T., et al., 2003. Rearing effects on cerebrospinal fluid
oxytocin concentration and social buffering in rhesus
monkeys. Neuropsychopharmacology 28, 910918.

232

brain research 1580 (2014) 219232

Wisner, K.L., Wheeler, S.B., 1994. Prevention of recurrent

postpartum major depression. Hosp. Commun. Psychiatry 45,
11911196.
Wisner, K.L., et al., 2006. Postpartum depression: a randomized
trial of sertraline versus nortriptyline. J. Clin.
Psychopharmacol 26, 353360.
Wisner, K.L., Moses-Kolko, E.L., Sit, D.K., 2010. Postpartum
depression: a disorder in search of a definition. Arch. Womens
Ment. Health 13, 3740.
Workman, J.L., Barha, C.K., Galea, L.A., 2012. Endocrine substrates
of cognitive and affective changes during pregnancy and
postpartum. Behav. Neurosci. 126, 5472.
World Health Organization, 1992. The ICD-10 Classification of
Mental and Behavioural Disorders: Clinical Descriptions
and Diagnostic Guidelines. World Health Organization,
Geneva.
Yatzkar, U., Klein, E., 2009. Intranasal oxytocin in patients with
post traumatic stress disorder: a single dose pilot double blind
crossover study. Clin. Neuropsychopharmacol 32, S84.

Yim, I.S., et al., 2009. Risk of postpartum depressive symptoms

with elevated corticotropin-releasing hormone in human
pregnancy. Arch. Gen. Psychiatry 66, 162169.
Yonkers, K.A., et al., 2008. Pharmacologic treatment of
postpartum women with new-onset major depressive
disorder: a randomized controlled trial with paroxetine.
J. Clin. Psychiatry 69, 659665.
Yonkers, K.A., et al., 2009. The management of depression during
pregnancy: a report from the American Psychiatric
Association and the American College of Obstetricians and
Gynecologists. Gen. Hospital Psychiatry 31, 403413.
Yoshida, M., et al., 2009. Evidence that oxytocin exerts anxiolytic
effects via oxytocin receptor expressed in serotonergic
neurons in mice. J. Neurosci 29, 22592271.
Zetzsche, T., et al., 1996. Nocturnal oxytocin secretion is reduced
in major depression. Biol. Psychiatry 39, 584.
Zonana, J., Gorman, J.M., 2005. The neurobiology of postpartum
depression. CNS Spectr 10, 792799, 805.